Dipeptidyl peptidase IV (DPP4) deficiency increases Th1-driven allergic contact dermatitis
Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. Clinical & Experimental Allergy
(Impact Factor: 4.77).
06/2011; 41(8):1098-107. DOI: 10.1111/j.1365-2222.2011.03778.x
CD26 or dipeptidyl peptidase IV (DPP4) is known to be involved in several immunological processes and has recently been reported to play a crucial role in the allergic responses of the lungs.
To explore the impact of DPP4 on the allergic response of the skin.
Skin biopsies from patients suffering from atopic dermatitis (AD) and healthy controls were investigated for the expression of CD26/DPP4. Furthermore, the functional impact of CD26 was investigated in two models of contact hypersensitivity using CD26/DPP4-deficient and wild-type rats. Dinitrochlorobenzene (DNCB) was used to induce a T helper type 1 (Th1)-dominated inflammation and toluene-2,3-diisocyanate for a Th2-pronounced inflammation. The inflammatory responses were determined by histological quantification, flow cytometry [fluorescence-activated cell sorting (FACS)], and an enzyme-linked immunosorbant assay (ELISA).
CD26/DPP4-expression was up-regulated in the lesional skin biopsies of patients compared with healthy controls as well as in both models of contact hypersensitivity. However, in the more Th2-driven model, a reduced inflammatory skin response was found in CD26/DPP4-deficient rats, analogous to the effects observed recently in a rat model of asthma. In partial contrast, there was an aggravation of local skin inflammation in CD26/DPP4-deficient rats under conditions of Th1-like skin inflammation.
The up-regulation of CD26 in atopic dermatitis represents a new finding, which has also been seen in other inflammatory skin diseases. However, tissue expression of CD26/DPP4 in immunological skin response can either be beneficial or aggravating, depending on a possible Th1/Th2 shift. This might have consequences for humans suffering from diabetes mellitus treated by DPP4 inhibitors, who have eczematous skin diseases as a co-morbidity.
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Available from: Stephan von Hörsten
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ABSTRACT: Many disease models have shown that, within the species rat, different strains are differentially susceptible to asthma-induced inflammation depending on the genetic background. Likewise, CD26/DPPIV-deficiency in asthmatic F344 rats has been shown to result in a less pronounced inflammation and in increased Treg cell influx into the lung compared to wild-types. The aim of the present study was to investigate whether the genetic background of the animals interferes with CD26/DPPIV-deficiency in a model of allergic-like inflammation, or whether the deficiency per se is the predominant regulator of the inflammation. Therefore, we hypothesized that CD26/DPPIV-deficient Dark Agouti (DA) rats also exhibit a less pronounced ovalbumin (OVA)-induced inflammation compared to wild-types.
After sensitisation with OVA, Al(OH)3 and heat-killed Bordetella pertussis bacilli, animals were challenged three times with 5% aerosolized OVA at intervals of 24 hours, i. e. on three consecutive days. 24 hours after the third challenge, animals were sacrificed and examined. In both wild-type and CD26/DPPIV-deficient rat groups, asthma induction led to 1) lung inflammation, 2) significantly increased eosinophil infiltration in the BALF, 3) significantly increased IgE serum levels, 4) a significant increase of inflammatory cytokines, 5) a significant increase of different T cell populations in the lungs and in their draining lymph nodes, as well as to 6) a significantly higher number of all T lymphocyte subtypes in the blood. Thus, the degree of the OVA-induced Th2-driven pulmonary inflammation was similarly pronounced in both wild-type and CD26/DPPIV-deficient DA rats.
Available from: Yoshimasa Aso
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CD26/DPP-4 is highly expressed by T cells, especially CD4+ T cells (T helper cells; Th) and may regulate the differentiation, maturation, or proliferation of these cells. We investigated the effects of sitagliptin, a DPP-4 inhibitor, on the absolute number and percentage of various subsets of circulating CD4+ T cells in patients with type 2 diabetes.
We enrolled 30 consecutive patients (16 women and 14 men) with type 2 diabetes in a prospective, randomized, open-label, blinded endpoint study. Eligible participants were randomly assigned at a 2:1 ratio to either a sitagliptin group (sitagliptin at 50mg/day) or an active control group (glimepiride at 1mg/day). Patients were followed for 12 weeks with monthly review. Peripheral blood mononuclear cells were examined by flow cytometry for intracellular expression of cytokines (IFN-γ as a marker of Th1cells, IL-4 for Th2 cells, and IL-17 for Th17 cells) and for expression of CD4, CD25, and Foxp3 (regulatory T cells [Treg]).
Both groups showed similar improvement of glycemic control. The total number of CD4+ T cells was decreased by treatment with sitagliptin, while it did not change in the control group. The number and percentage of Th17 cells and Treg cells both decreased significantly in the sitagliptin group, but not in the control group. There was a significant positive correlation between changes in the percentage of Th17 cells and Treg cells after treatment with sitagliptin.
Treatment with sitagliptin for 12 weeks reduced the number of circulating CD4+ T cells, especially Th17 and Treg cells, in patients with type 2 diabetes.
Available from: Dorota Piekutowska-Abramczuk
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Mucopolysaccharidoses (MPS) are a group of rare, inherited metabolic disorders which result from the lack of one of the lysosomal enzymes responsible for the degradation of glycosaminoglycans. Early recognition of MPS is important as it enables prompt implementation of enzyme replacement therapy (ERT). Dipeptidyl peptidase-IV (DPP-IV) is a ubiquitous ectopeptidase which activity has been associated with the cell surface protein CD26. Our aims were to investigate plasma DPP-IV activity in untreated patients with MPS type II in comparison to control individuals and to evaluate changes of DPP-IV during ERT in MPS I or II patients.
Design and methods:
One MPS I and five MPS II patients were treated with ERT for up to 19months. DPP-IV activity was measured in plasma with a colorimetric method using Gly-Pro-p-nitroanilide as a substrate. The reference intervals were observed in 17 healthy donors and in 9 MPS II individuals before ERT implementation.
DPP-IV activity ranged from 557 to 1959nmol/ml/h (median and interquartile range: 1453 [955-1554], n=17) in plasma of control samples. In 9 untreated MPS II individuals, DPP-IV activity was higher and ranged from 2565 to 5968nmol/ml/h (median and interquartile range: 4458 [4031-5161]). In 6 MPS patients receiving ERT, DPP-IV activity ranged from 2984 to 8628nmol/ml/h. No declining tendency was observed during the treatment.
DPP-IV activity is a good, new and valuable biomarker distinguishing between MPS and healthy individuals. However, it is not a useful marker of treatment efficacy and is unsuitable for monitoring.
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